This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Studies of the PD-1 molecule on CD4+ and CD8+ T cells performed on uninfected and SIV infected rhesus macaques revealed 3 major findings: A) rapid upregulation of PD-1 expression on tetramer positive CD8+ T cells from MamuA.01+ SIV infected macaques early post infection while upregulation of PD-1 on total CD8+ T cells was undetectable. B) In contrast, CD4+ T cells PD-1 expression was markedly higher in total CD4+ T cells during chronic infection and c) there was a correlation between the level of PD-1 expression on naive and central memory CD4+ T cells and the levels of viral loads. There was marked decrease of PD-1 expression on tetramer positive CD8+ and CD4+ T cells shortly after initiation of antiretroviral therapy and downregulation of viral replication. We have cloned rMamu PD-1 and fused it to a modified Rhesus IgG2 Fc molecule that is unable to bind complement or FcR on NK cells. SIV specific proliferation of CD8 but predominantly CD4 T cells from chronically infected monkeys was markedly amplified with the addition of PD-1 antagonist in a dose dependent manner. We will address the effect of PD-1-ligand blockade first in vitro on CD4 and CD8+ T cells as well as the role of PD-1 ligation on Treg cells and the potential DC responsible for such signaling. We will also block the PD1-ligand interaction during early and late chronic SIV infection in to investigate if therapeutic attempts have the capability of restoring anti-viral CD4 and CD8+ T cell effectors responses.